Tricyclo-DNA nucleoside precursors and processes for preparing the same

Abstract

The present invention relates to a process for preparing tc-DNA nucleoside precursors, the resulting tc-DNA nucleosides, and oligonucleotides comprising such tc-DNA nucleosides. In an embodiment of the invention, the process includes use of a carbene precursor. In an embodiment, the invention includes processes for preparing a tc-DNA nucleoside precursor of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI).

We claim: 
     
       1. A method of preparing a tc-DNA nucleoside precursor of any one of Formulas I-III: 
       
         
           
           
               
               
           
         
         the method comprising the steps of: 
         a. preparing a carbene precursor at a carbene preparation temperature, wherein the step of preparing the carbene precursor comprises combining a first Lewis acid and R 7 I 2  in a solvent, wherein R 7  is selected from the croup consisting of CH 2 , CH—C 1-6 alkyl, CH—C 2-6 alkenyl, CH—C 2-6 alkynyl, substituted CH—C 1-6 alkyl, substituted CH—C 2-6 alkenyl, substituted CH—C 2-6 alkynyl, and CH-(CH 2 ) n —C(O)-R 8 , wherein n is 0 to 6 and wherein R 8  is selected from the croup consisting of OH, NH 2 , O-C 1-32 alkyl and NH-C 1-32 alkyl; 
         b. mixing the carbene precursor with a compound of Formula X, Formula XI, or Formula XII: 
       
       
         
           
           
               
               
           
         
         at a cyclopropanation temperature; and 
         c. adding a catalytic amount of a second Lewis acid to the mixture;
 wherein X and Y are each alkoxy; 
 T 1 , T 2 , T 3  and T 4  are each OR 5 , where each R 5  is H or a hydroxyl protecting group; 
 q 5 , q 6 , and q 7 , and q 8  are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, substituted C 1-6 alkyl, substituted C 2-6 alkenyl, substituted C 2-6 alkynyl, and —(CH 2 ) n —C(O)-R 6 , wherein n is 0 to 6 and wherein R 6  is selected from the group consisting of OH, NH 2 , O-C 1-32 alkyl and NH-C 1-32 alkyl; 
 q 8  is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 2 -3alkenyl, C 2-3 alkynyl, substituted C 1-3 alkyl, substituted C 2-3 alkenyl, substituted C 2-3 alkynyl, and —(CH 2 ) n —C(O)—R 6 , wherein n is 0 to 2 and wherein R 6  is selected from the group consisting of OH, NH 2 , O-C 1-3 alkyl and NH-C 1-3 alkyl; and 
 z 3  and z 4  are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, substituted C 1-6 alkyl, substituted C 1-6 alkoxy, substituted O-C 2-6 alkenyl, and substituted O-C 2-6 alkynyl halogen. 
 
       
     
     
       2. The method of  claim 1 , wherein the tc-DNA nucleoside precursor is any one of Formulas IV-IX: 
       
         
           
           
               
               
           
         
       
     
     
       3. The method of  claim 1 , wherein the solvent comprises hexanes, toluene, dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), acetonitrile (CH 3 CN), dimethylformamide (DMF), diethylether, dimethoxyethane (DME), or a combination thereof. 
     
     
       4. The method of  claim 1 , wherein the step of preparing the carbene precursor includes the step of adding a carbene additive to the mixture of Lewis acid catalyst and R 7 I 2 , wherein the carbene additive is selected from the group consisting of substituted or unsubstituted alkyl alcohol, carboxylic acid, and phosphate. 
     
     
       5. The method of  claim 1 , wherein the carbene precursor is Q 3 CCO 2 ZnR 7 I, Q 3 CCH 2 OZnR 7 I, (n-BuO) 2 P(O)OZnR 7 I, (alkyl-O) 2 P(O)OZnR 7 I, (aryl-O) 2 P(O)OZnR 7 I, or 2,4,6-Cl 3 C 6 H 2 OZnR 7 I, wherein each Q is independently selected from the group consisting of H, Cl, Br, and F, and R 7  is selected from the group consisting of CH 2 , CH—C 1-6 alkyl, CH—C 2-6 alkenyl, CH—C 2-6 alkynyl, substituted CH—C 1-6 alkyl, substituted CH—C 2 -6alkenyl, substituted CH—C 2-6 alkynyl, and CH—(CH 2 ) n —C(O)—R 8 , wherein n is 0 to 6 and wherein R 8  is selected from the group consisting of OH, NH 2 , O-C 1-32 alkyl and NH—C 1-32 alkyl. 
     
     
       6. The method of  claim 1 , wherein the carbene precursor is CCl 3 CO 2 ZnCH 2 I, CF 3 CH 2 OZnCH 2 I, (n-BuO) 2 P(O)OZnCH 2 I, or 2,4,6-Cl 3 C 6 H 2 OZnCH 2 I. 
     
     
       7. The method of  claim 1 , wherein the first Lewis acid and the second Lewis acid are each independently selected from the group consisting of Et 2 AlCl, Et 2 Zn, ZnI 2 , ZnCl 2 , ZnBr 2 , Ti(OiPr) 4 , Me 2 AlCl, TMSOTf, TiCl 4 , and combinations thereof. 
     
     
       8. The method of  claim 1 , wherein the first Lewis acid is Et 2 Zn. 
     
     
       9. The method of  claim 2 , wherein the solvent comprises hexanes, toluene, dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), acetonitrile (CH 3 CN), dimethylformamide (DMF), diethylether, dimethoxyethane (DME), or a combination thereof. 
     
     
       10. The method of  claim 2 , wherein the step of preparing the carbene precursor includes the step of adding a carbene additive to the mixture of Lewis acid catalyst and R 7 I 2 , wherein the carbene additive is selected from the group consisting of substituted or unsubstituted alkyl alcohol, carboxylic acid, and phosphate. 
     
     
       11. The method of  claim 2 , wherein the carbene precursor is Q 3 CCO 2 ZnR 7 I, Q 3 CCH 2 OZnR 7 I, (n-BuO) 2 P(O)OZnR 7 I, (alkyl-O) 2 P(O) OZnR 7 I, (aryl-O) 2 P(O)OZnR 7 I, or 2,4,6-Cl 3 C 6 H 2 OZnR 7 I, wherein each Q is independently selected from the group consisting of H, Cl, Br, and F, and R 7  is selected from the group consisting of CH 2 , CH—C 1-6 alkyl, CH—C 2 -6alkenyl, CH—C 2-6 alkynyl, substituted CH—C 1-6 alkyl, substituted CH—C 2-6 alkenyl, substituted CH—C 2-6 alkynyl, and CH-(CH 2 ) n-C(O)—R 8 , wherein n is 0 to 6 and wherein R 8  is selected from the group consisting of OH, NH 2 , O—C 1-32 alkyl and NH—C 1-32 alkyl. 
     
     
       12. The method of  claim 2 , wherein the carbene precursor is CCl 3 CO 2 ZnCH 2 I, CF 3 CH 2 OZnCH 2 I, (n-BuO) 2 P(O)OZnCH 2 I, or 2,4,6-Cl 3 C 6 H 2 OZnCH 2 I. 
     
     
       13. The method of  claim 2 , wherein the first Lewis acid and the second Lewis acid are each independently selected from the group consisting of Et 2 AlCl, Et 2 Zn, ZnI 2 , ZnCl 2 , ZnBr 2 , Ti(OiPr) 4 , Me 2 AlCl, TMSOTf, TiCl 4 , and combinations thereof. 
     
     
       14. The method of  claim 2 , wherein the first Lewis acid is Et 2 Zn.